The causes of alcoholism are both genetic and environmental: the most likely explanation is an interaction between genes and environment resulting in excessive drinking. Although animals can only model certain aspects of alcoholism, the experimenter can control both their genetics and environment, leading to better understanding of how these variables and their interaction cause high drinking. In this proposal, we seek to maintain lines of mice selectively bred to either freely drink a relatively large amount of alcohol (High Alcohol Preferring, o1:HAP), or abstain (Low Alcohol Preferring, or LAP). To allow reliable comparisons between high and low drinkers, two populations of both high and low drinkers will be bred. We will also develop a new, very high drinking line by crossing the two high drinking lines. These mice will be useful for both genetic and behavioral studies. Previously, HAP mice were shown to be more likely than LAP mice to develop increased sensitivity to activating effects of alcohol following repeated experience. In HAP mice, alcohol experience also increased subsequent alcohol drinking. This proposal will seek to better understand the causes and consequences of increased alcohol sensitivity, and why HAPs are more likely to show it. First, this proposal will assess whether the increase in activity in HAPs might result from tolerance to the incoordinating effects of alcohol. Second, studies will assess whether experience with alcohol increases sensitivity to other activating drugs, such as cocaine. Such studies can model why many human alcoholics often turn to other drugs of abuse. Third will be study of whether HAP mice show more sensitization than LAP mice to drugs other than alcohol, to assess whether the genes which cause high drinking affect how the brain adapts to many drugs of abuse. Additional work in this grant will develop a new behavioral model to assess alcohol seeking and craving behavior, thought to be important in alcoholism. We will assess whether mice bred to drink large quantities of alcohol will also show more alcohol seeking when they must work to gain access to alcohol solutions. By comparing these lines, and manipulating the environment, this proposal will increase understanding of how genes for high drinking interact with drug and alcohol experience to promote further drinking.